1. Field of the Invention
The invention relates to the preparation of novel cyclisation substrates for steroidal compounds, and also relates to the conversion of these cyclisation substrates substrates into novel steroidal compounds, in particular, 11.alpha.-substituted steroids of the oestrane series.
2. Related Applications
This application is related to Ser. No. 880,151, filed Feb. 22, 1978, to Ser. No. 880,153, filed Feb. 22, 1978, issued on Dec. 4, 1979, as U.S. Pat. No. 4,177,197 and to an application entitled "CYCLISATION SUBSTRATES AND RELATED 11.beta.-AXIALLY SUBSTITUTED STEROIDS" Ser. No. 953,790, filed Oct. 23, 1978.
3. Prior Art and Other Information
The 11.alpha.-alkyl-19-nor-steroids are biologically active compounds to which access by synthetic routes is difficult for those in the art. For example, in 41 J. ORG. CHEM 531 (1976), an unsuccessful attempt is described to prepare 11-alkyl-substituted steroids by a total synthesis according to the method of Torgov. The cyclisation by the Johnson method of 2-(5'7'-dimethyl-trideca 3'(E),7'(E)-dien-11-ynyl)-3-methyl-cyclopent-2-enol to 11-methyl-steroids is described in the dissertation of T. M. Yarnell, (Stanford University, July 1975, in DISSERTION ABSTRACTS INTERN, B 36 (1976) no. 10 at page 5054. The 5'-methyl group in the cyclisation substrate is the "pro-C-11" substituent. In this cyclisation, in addition to a range of other products, the 11.alpha.-methyl-steroid and the 11.beta.-methyl-isomer were shown to be formed in approximately equal proportions. Stereo-selectivity was described as absent, and this synthesis therefore had little practical value.
Also, Johnson discloses in U.S. Pat. No. 4,032,579 various cyclopentenyl alcohols which can be cyclized to 11-chalcogen-substituted steroids (see especially col. 17, line 64 to col. 20, line 12), although there is no disclosure of an A-ring intermediate. Hughes (U.S. Pat. Nos. 3,417,105 and 3,547,909) disclose aryl cyclopentanediones which are cyclized to gonene compounds. Bertin et al (U.S. Pat. No. 3,526,648) and Bucourt (U.S. Pat. No. 3,906,096 discloses 11.beta.-alkoxy steroids.
Of interest also is U.S. Pat. No. 3,778,434 to Coombs, directed to the preparation of 9.alpha.,11-dimethyl-substituted estranes from the corresponding estane-17-ones.
The stereospecific cyclisation of a compound of formula XX: ##STR3## where R=CH.sub.3 into a compound of formula XXI: ##STR4## where R=CH.sub.3 is described in 98 J.A.C.S. 1038 (1976).
Only the equatorial 11.alpha.-methyl derivative is formed. The cyclisation of a (pro)-11-hydroxy compound also results exclusively in the 11.alpha.-hydroxy steroid (98 J.A.C.S. 1038-1039 1976)).
Again it is mentioned that when this cyclisation is performed in the (pro)-19-nor-series (R is H), it proves that no stereo-selectivity occurs (see T. M. Yarnell, Dissertion, Stanford University, July 1975, in 1976 DISSERTATION ABSTRACTS INTERN, 1976, B35 no. 10, page 505 4). A mixture 11.alpha.- and 11.beta.-substituted steroids in molar proportions of about 1:1 is formed.
Distantly related compounds by structure (7-substituted compounds) to those of formulae II-III of the instant invention are disclosed in Anner et al, U.S. Pat. No. 3,660,435 (7.alpha.-methyl-3,16.alpha.,17.alpha.-trihydroxy-.DELTA..sup.1,3,5(10) -oestratrienes for controlling fertility) and U.S. Pat. No. 3,804,866 (3-cyclopentyl ether of 7.alpha.-methyl-3,16.alpha.,17.alpha.,.beta.-trihydroxy-.DELTA..sup.1,3,5( 10) oestratrienes and their 16,17-diacetates for controlling fertility. See also U.S. Pat. No. 3,345,570 (to Anner et al (isolation of 7.alpha.-methyl-3-oxo-.DELTA..sup.4 steroids from mixtures of the epimeric 7-methyl-compounds); U.S. Pat. No. 3,627,894 to Babcock (novel 7.alpha.-methylestrones); U.S. Pat. No. 3,928,398 to Grunwell et al (7.alpha.methylestr-4-ene-3.alpha.,17.beta.-diols as antiprogestational and antifertility agents); U.S. Pat. No. 3,574,197 (1-hydroxy-7.alpha.-methyl-estranes); U.S. Pat. No. 3,944,576 (7.alpha.-methoxymethyl-estranes); and U.S. Pat. Nos. 3,318,925/26/27/28/29 (7.alpha.-methyl-.DELTA..sup.1,3,5(10) -estratrienes).
A method of producing analogues of the compounds (II, III) unsubstituted in ring C, is disclosed in British Pat. No. 1,448,873 (producing oestrone by cyclizing 2-[(E)-6-aryl-3hexenyl]cyclopentenols of which the hexenyl group has not been substituted).
See also 95 J.A.C.S. 7501-7504 (1973).
The following stereo-selective synthesis was described in 22 Tetrahedron at 1019-1025 (1966): ##STR5## The main product obtained was the 6.beta.-methyl compound (yield 25%-40% by weight) in addition to traces of the 6.alpha.-methyl compound. Since the 6.alpha.-methyl compounds are the most valuable, attempts were made to isomerise the 6.beta.-methyl compounds to 6.alpha.-methyl compounds, after the A-ring had been converted to a 3-oxo-.DELTA..sup.4 -system: ##STR6##
This isomerisation occurs only in part, and the 6.alpha.-methyl compound can only be obtained in low yield by this route. The circuitous route via the enol acetate gives higher yields (see 90 Recueil 849 (1971)).
Other distantly related art by structure (6-substituted) includes U.S. Pat. No. 3,137,689 to Dorfmann et al, which teaches preparation of 6.alpha.-methyl-pregnenolones (antiovulatory activity); U.S. Pat. No. 3,257,427 to Bowers for 6-alkyl-3-desoxy-.DELTA..sup.1,3,5(10) estratriene substituted in the 17 position by keto or hydroxy (anti-androgenic action, low feminizing effects; for fertility control and menstrual disorders); U.S. Pat. No. 3,816,481 to Douglas et al for 6.alpha.-methyl-4-gonenes (progestational activity); and British Pat. No. 1,448,873 (cyclisation of (arylhexenyl)-cyclopentenols to .DELTA..sup.1,3,5(10),13(17) gonatetraenes unsubstituted in position 6).